Phenotypic screening of a full compound library… A reality or a pipe(line) dream?

The search for new drugs is getting increasingly more difficult. This is due to a variety of factors, but the main ones are: the ‘low hanging fruit’ has already been identified and the regulatory hurdles to overcome are becoming ever more numerous and becoming increasingly more difficult to pass. This has resulted in a high rate of attrition, with many candidates failing very late in clinical trials due to safety/toxicity concerns as opposed to lack of efficacy, incurring enormous financial losses. This resultant decrease in R&D productivity has placed the pharmaceutical industry under immense pressure to find better ways to bring new drugs to market. Of the drugs that are approved, many are follower drugs. This is in stark contrast to the real goal of drug research which is to identify a first in class molecule. As a result, strategies for screening to identify more and better lead compounds are constantly evolving.

So why are there so few truly novel medicines coming through the pipeline? There are many possible answers, but a couple of interest are: is the screening pool from which we select compounds just too small, or not chemically diverse enough and are we just not using the best methods to select quality hit compounds?